Most of the information available at present about the biological underpinnings of cocaine effects derives from animal studies. These studies have shown that the dopaminergic system plays an important role in many of cocaine effects but that this role is not exclusive. Cocaine has a diversity of neurochemical actions involving the nonadrenergic and serotonergic systems as well as other neurotransmitter systems whose role still remains somewhat undetermined. The wealth of preclinical data on neurotransmitter alterations associated with cocaine administration is not matched by information derived from human studies. in man, much is known about the epidemiology of cocaine use, about its patterns of use and about the psychopathology associated with its consumption and discontinuation but our knowledge of neurochemical alterations underlying cocaine actions is still lagging. Information about neurochemical alterations preceding cocaine abuse is also extremely scarce. In order to gain information about the serotonergic function of individuals who engage in a lifestyle of cocaine abuse we studied their responsivity to challenges with a postsynaptic partial agonist, meta- chlorophenylpiperazine (mCPP) and compared it to the responsivity of healthy volunteers. Cocaine abusers differed significantly from control subjects. They displayed a psychological hyperresponsivity and a neuroendocrine hyporesponsivity to m-CPP. Associations were also found between personality characteristics indicating a poor impulse, mood and aggression control and psychological changes observed in response to m- CPP. These data could indicate that serotonin plays a role in the pathogenesis of cocaine addiction, at least in some individuals. The effects of cocaine itself could however not be assessed because our subjects were studied only once during the second week of an inpatient stay. The present proposal involves sequential assessments following cocaine discontinuation of the serotonergic function of individuals whose drug of choice has been cocaine for at least 3 years and who have used cocaine exclusively for a period of 6 months prior to the start of the study. The serotonergic function will be assessed through challenges with m-CPP and an indirect serotonin agonist, fenfluramine (FEN). Personality assessments will be done and psychological and neuroendocrine responses to m-CPP and FEN assessed first after admission to an inpatient rehabilitation unit and 4 days after cocaine discontinuation, and again prior to discharge, 3 weeks later. Patients will then be followed for a period of 6 months to see whether any of the assessments outlined above predicts clinical course and outcome. The study we propose to do will give us information about disturbances in a neurotransmitter system believed to play a significant role in cocaine actions, about the persistence of neurotransmitter alterations after a cocaine free period of 3 to 4 weeks, about the role played by premorbid characteristics in neurotransmitter function in cocaine addicts and about the predictive values of psychological and biological alterations on clinical course 6 months later. One can hypothesize that there is an interplay between predisposing neurochemical alterations and the superimposed effects of cocaine. Cocaine addicts could be biologically heterogeneous and treatment needs might be different in subgroups of patients with different psychopathological and biological profiles.